Neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. Antibodies given intravenously can protect macaques against intravenous or mucosal SHIV challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. The mechanisms of this protection are not understood. It is often assumed that neutralization of free virus particles, as measured in classical in vitro assays, is solely responsible because protection is afforded by neutralizing antibodies. However neutralizing antibodies can also mediate a number of other anti-viral activities, notably against infected cells. These include effector functions such as complement activation and antibody dependent cellular cytotoxicity mediated by the Fc part of the antibody molecule. The critical importance of effector functions for antibody-mediated protection against a number of viruses has been well documented in the literature. The purpose of this application is to explore the importance of effector function in antibody-mediated protection against HIV. It is proposed to investigate the ability of a panel of antibody molecules, derived from the human neutralizing antibody IgG1b12, to protect against vaginal challenge with an R5 SHIV in macaques. The conditions for intravenously or topically administered IgG1b12 to protect against vaginal challenge have been established previously. The current application makes use of a panel of IgG1 b12variants in which effector functions have been specifically disabled to better understand the role of effector functions in systemic and mucosal antibody-mediated protection. In addition, a secretory IgA version of b12 (SIgA2b12) will be used to compare the ability of mucosal IgA and IgG to protect and to reveal the importance of functions associated with SIgA in protection. The results will help clarify how antibodies protect against HIV and may have implications for vaccine design and microbicide development. [unreadable] [unreadable] [unreadable]